Persistent Infection Research Articles

IN VITRO ANTIBACTERIAL ACTION OF ZINGIBER OFFICINALE ROSCOE CRUDE EXTRACT IRRIGATION AGAINST STAPHYLOCOCCUS AUREUS ISOLATED FROM INFECTED HUMAN ROOT CANALS

Root canal irrigating solutions with strong antibacterial properties are crucial for effective endodontic therapy by preventing recurrent and persistent infections. The question now is not so much whether microbes play a role in the pathophysiology of pulpitis and apical periodontitis, but rather whether species of microbes play a role. The list of microorganisms linked to periodontitis is still growing and could get more precise in future years. Conventional antibacterial agents such as sodium hypochlorite (NaOCl) have failed to overcome a variety of Staphylococcus aureus moreover its toxicity and the occasional report of pain when higher concentrations are used. 7 S. aureus strains were isolated from infected root canals and identified using the VITEK® 2 compact system. An aqueous crude extract of Zingiber officinale Roscoe was prepared and used as a safe and effective antibacterial agent against the S. aureus isolates and S. aureus ATCC 25923. The gas chromatography-mass spectrometry (GC-MS) analysis of Z. officinale Roscoe extract exhibits 14 different biochemical compounds including gingerol (46.11%), zingiberene (17.12%), and thymol (11.20%) as the main constituents. The antibacterial activity of Z. officinale Roscoe extract and NaOCl was investigated against S. aureus strains compared to ciprofloxacin as a standard drug using agar well diffusion method, minimum inhibition zone concentration (MIC), and minimum bactericidal concentration (MBC). The Z. officinale Roscoe extract revealed higher antibacterial activity than NaOCl and ciprofloxacin with inhibition zones averages of 18 ± 0.03, 16 ± 0.06, and 15 ± 0.14 mm, respectively. The MIC and MBC values of Z. officinale Roscoe extract were 40 and 40 µg/mL compared to NaOCl (55 and 65 µg/mL, respectively). This study provides an alternate antibacterial irrigation root canal solution, Z. officinale Roscoe extract against human pathogenic S. aureus.

Multitargeted docking approach reveals droxidopa against DNA replication and repair-related protein of cervical cancer

Cervical cancer begins in the cells lining the cervix and is caused by persistent infection with certain types of human papillomavirus (HPV). Initially, it has no symptoms, and later it causes pelvic pain, abnormal vaginal bleeding, and pain during intercourse. It is the fourth-ranked cancer among women, and many women die from cervical cancer every year, particularly in low-income countries and the majority could be prevented with early detection and treatment. In this study, we have taken Cervical Cancer DNA Replication and Repair-Related Protein with the PDBID- 3H15, 5VBN, and 6NT9 and performed the multitargeted molecular docking with the FDA-approved drug library using HTVS, SP and XP docking. Then, the poses were filtered with MM\\GBSA for proper computations of free energy, identified a multitargeted inhibitor Droxidopa with docking and MM\\GBSA scores ranging from − 5.559 to − 6.835 Kcal/mol and − 26.04 to − 37.33 Kcal/mol, respectively. We also performed interaction fingerprints revealing 2VAL, 2LYS, 1ALA, 1ARG, 1ASN, 1CYS, 1GLN, 1GLU, 1ILE, 1MET, 1PHE, 1PRO, 1SER, and 1THR were most interacted residues and computed the ADMET properties with QikProp and DFT with Jaguar, which supported the study and compounds’ suitability. Moreover, we performed the 100ns MD simulation in water, showing the controlled deviation and fluctuations of the residues with many interactions, and MM\\GBSA was performed with the same trajectories, showing a better understanding of each frame’s total complex and binding-free energy. The whole study favours droxidopa as an inhibitor of cervical cancer DNA Replication and Repair-Related Proteins—however, experimental studies are needed before use.

Macrolide resistance through uL4 and uL22 ribosomal mutations in Pseudomonas aeruginosa

Macrolides are widely used antibiotics for the treatment of bacterial airway infections. Due to its elevated minimum inhibitory concentration in standardized culture media, Pseudomonas aeruginosa is considered intrinsically resistant and, therefore, antibiotic susceptibility testing against macrolides is not performed. Nevertheless, due to macrolides’ immunomodulatory effect and suppression of virulence factors, they are used for the treatment of persistent P. aeruginosa infections. Here, we demonstrate that macrolides are, instead, effective antibiotics against P. aeruginosa airway infections in an Air-Liquid Interface (ALI) infection model system resembling the human airways. Importantly, macrolide treatment in both people with cystic fibrosis and primary ciliary dyskinesia patients leads to the accumulation of uL4 and uL22 ribosomal protein mutations in P. aeruginosa which causes antibiotic resistance. Consequently, higher concentrations of antibiotics are needed to modulate the macrolide-dependent suppression of virulence. Surprisingly, even in the absence of antibiotics, these mutations also lead to a collateral reduction in growth rate, virulence and pathogenicity in airway ALI infections which are pivotal for the establishment of a persistent infection. Altogether, these results lend further support to the consideration of macrolides as de facto antibiotics against P. aeruginosa and the need for resistance monitoring upon prolonged macrolide treatment.

Prostaglandin E2 suppresses KCNH1 gene expression and inhibits the proliferation of CaSki cervical cells through its four prostanoid PTGER subtypes

The main risk factor for cervical cancer is the persistent infection of high-risk HPV subtypes, notably HPV16. Another contributing factor is proinflammatory prostaglandin E2 (PGE2), a lipid abundantly found in seminal fluid. PGE2, along with its receptors (PTGER1-4), contributes to cancer development; however, its specific role in the proliferation of cervical cancer models with high HPV16 copy numbers remains unclear. In this study, we investigated the effects of PGE2 on the proliferation of CaSki cells, a cell line with a high HPV16 viral load. Surprisingly, PGE2 inhibited CaSki cell proliferation, while it increased the proliferation of SiHa, HeLa, and C-33 A cervical cancer cells. The effect of PGE2 on CaSki cell proliferation was specific, as estradiol increased cell growth. Furthermore, PGE2 suppressed expression and promoter activity of the cervical tumoral marker KCNH1. To discern the specific role of each receptor in cell proliferation, we generated stable CaSki cell lines overexpressing each receptor alongside control cells with an empty vector. Notably, PGE2 significantly inhibited cell proliferation in all stable transfected CaSki cells, suppressing oncogenic KCNH1 expression and its promoter activity. In conclusion, our findings indicate that PGE2 inhibits the proliferation of CaSki cervical cancer cells with a high HPV16 load, at least in part, by suppressing the expression of the oncogenic KCNH1 gene.

Investigating Sortase A inhibitory potential of herbal compounds using integrated computational and biochemical approaches

Multi-drug resistance in bacteria is emerging as a major global health challenge, causing substantial harm in terms of mortality, morbidity, and financial strain on healthcare systems. These bacteria are constantly acquiring new virulence factors and drug-resistance mechanisms, which highlights the critical need for innovative antimicrobial medicines and identification of new therapeutic targets, such as Sortase A (EfSrtAΔN59). EfSrtAΔN59, a transpeptidase significant for the adhesion and virulence of Enterococcus faecalis (E. faecalis), presents an attractive target for disrupting biofilm formation—a key factor in persistent infections. This study investigates the inhibitory effects of two natural flavonoids- Rutin Trihydrate and Quercetin, on EfSrtAΔN59 and biofilm formation in E. faecalis. With in vitro enzymatic assays and biofilm quantification techniques, we demonstrate that both compounds significantly attenuate EfSrtAΔN59 activity, thereby hindering bacterial biofilm formation. Rutin Trihydrate and Quercetin exhibited strong binding affinities to the EfSrtAΔN59 enzyme, as confirmed by molecular docking and MD simulation studies. This was further substantiated by a notable reduction in biofilm biomass in bacterial cultures treated with these compounds. These findings highlight the potential of Rutin Trihydrate and Quercetin as promising candidates for the development of novel anti-virulence therapies aimed at mitigating E. faecalis infections, thereby offering a compelling alternative to traditional antibiotics.

Antibacterial Activity of Ethanol Extract of Aceh Patchouli Leaves (Pogostemon cablin Benth.) against Enterococcus faecalis: A Potential Alternative for Root Canal Infections

The persistence of bacterial infections and antibiotic resistance in secondary root canal infections necessitate effective antimicrobial approaches utilizing natural compounds. This study aimed to evaluate the extraction efficiency, phytochemical composition, and antibacterial activity of the ethanol extract of Aceh patchouli leaves (Pogostemon cablin Benth.) against Enterococcus faecalis. The maceration method was employed for extraction and phytochemical analysis was conducted using gas chromatography-mass spectrometry (GC-MS). Antibacterial activity was assessed using the Kirby-Bauer method, and the minimum inhibitory concentration (MIC) was determined using UV-vis spectrophotometry. The results indicated a total extract yield of 17.25 % and significant antibacterial activity against E. faecalis. The active compounds in the extract were primarily sesquiterpenes and fatty acids, with patchouli alcohol as the most prominent. The MIC value was 12.5 %, suggesting the potential of Aceh patchouli extract as an alternative or adjunctive treatment for root canal infections. This study has the potential to make Aceh's indigenous Pogostemon cablin Benth. plant as an alternative or adjunctive treatment for root canal infections leading to safe and effective treatments that minimize the risk of antibiotic resistance. HIGHLIGHTS The ethanol extract of Aceh patchouli leaves (Pogostemon cablin Benth.) was obtained using the maceration method, yielding a total extract value of 17.25 %. The active compounds of the extract were primarily sesquiterpenes and fatty acids, with patchouli alcohol being the most prominent. The ethanol extract exhibited significant antibacterial activity against Enterococcus faecalis, a common bacterium responsible for secondary root canal infections. The MIC of the extract was 12.5 %, indicating its potential effectiveness as an antimicrobial agent. This study suggests that the Aceh patchouli leaves could serve as an alternative or adjunctive treatment for root canal infections, addressing the challenges of bacterial persistence and antibiotic resistance. GRAPHICAL ABSTRACT

Single-center study of COVID-19 in patients with chronic lymphocytic leukemia

Objective: To investigate the vaccination status, characteristics and prognosis of patients suffering from a combination of COVID-19 and chronic lymphocytic anemia (CLL) in China. Methods: Clinical data of 328 patients with chronic lymphocytic leukemia (CLL) who were first diagnosed with COVID-19 and treated in the Department of Hematology of Jiangsu Provincial People's Hospital between November 2022 and February 2023 were retrospectively analyzed. Univariate and multivariate analysis of data of patients with severe/critical COVID-19 were conducted by applying the binary logistic regression model. Results: The median age of the CLL patients was 60 (24-87) years. 23.5% (77/328) of these patients suffered from severe/critical COVID-19 infection. Univariate analysis of the data demonstrated that a combination of factors including age >67 years (OR=2.15, 95% CI 1.24- 3.73, P=0.006), diabetes (OR=2.09, 95% CI 1.05-4.20, P=0.037), chronic hepatitis B (OR=2.91, 95% CI 1.30-6.51, P=0.010), CLL progressive (OR=3.79, 95% CI 1.57-9.15, P=0.003) and CD20 antibody-based treatments within three months prior to the COVID-19 infection (OR=2.79, 95% CI 1.35-5.77, P=0.006) were the risk factors for severe/critical COVID-19. According to the multivariate analysis, CLL progressive (OR=2.98, 95% CI 1.10-8.10, P=0.033) was an independent risk factor for severe/critical COVID-19 and administration of the BTK (Bruton tyrosine kinase) inhibitor monotherapy might exert a protective effect and influence a positive outcome of the COVID-19 infection (OR=0.38, 95% CI 0.16-0.90, P=0.028). Among the 242 patients who were followed up until October 2023, 9.1% (22/242) had multiple subsequent COVID-19 infections (≥3), and 2.1% (5/242) had persistent COVID-19 infections (patients with persistent positive test for the SARS-CoV-2 antigen testing until missing follow-up for any reason). The peak value of the anti-SARS-CoV-2-IgG titres was observed between three and four months post symptom onset (median: 3.511 S/CO vs 1.047 S/CO, P<0.05). The levels of immunoglobulin A gradually decreased following infection with COVID-19, and its trough levels were attained between two to four weeks post infection (median: 0.30 g/L vs 0.74 g/L, P<0.05). According to this study the mortality of patients suffering from a combination of COVID-19 infection and CLL was 2.7% (9/328), and the main reason for their death was respiratory failure and heart failure. Conclusions: A low rate of COVID-19 vaccination and a high rate of severe/critical COVID-19 infection was observed in the CLL patients. CLL progressive was associated with severe/critical COVID-19. Anti-CD20-based treatments received within the past three months might be a risk factor for exacerbation of COVID-19 infection, whereas a monotherapy with BTK inhibitors exert a protective effect and improve outcome of COVID-19 infection.

PH‐sensitive size/surface charge‐adaptive quaternary ammonium salt copolymer micelles for antibiofilm activity against Staphylococcus aureus

AbstractThe low penetration of antibacterial materials within biofilms results in a 1000‐fold decrease in bactericidal efficiency, complicating the complete removal of biofilms and potentially leading to persistent and recurrent bacterial infections that significantly impact human health. In this study, we present a multifunctional pH‐responsive antibacterial material based on random copolymers poly(dimethylaminoethyl methacrylate decyl ammonium bromide‐co‐polyethylene glycol methacrylate) copolymer (PQACs10‐co‐PEGMA10). The PQACs10‐co‐PEGMA10 copolymers could self‐assemble into micelles in selective solvent water. With the stealth function of polyethylene glycol (PEG), the PQACs10‐co‐PEGMA10 micelles can rapidly penetrate biofilms in a physiological environment and exhibit excellent antibacterial activity by exposing the quaternary ammonium salt (QACs) in an acidic microenvironment to eliminate biofilm. Furthermore, PQACs10‐co‐PEGMA10 micelles were applied as coatings using a dropwise method. The PEG chain formed hydration layer and the QACs chain for sterilization can hinders bacterial adhesion and proliferation, thereby preventing biofilm formation. The results show that the minimal inhibit concentration values and minimum biofilm eradication concentrations of the PQACs10‐co‐PEGMA10 micelles against Gram‐positive Staphylococcus aureus were 64 and 128 μg/mL, respectively. The antifouling and antibacterial rates of micelle coating against S. aureus were more than 99.99%. Taken together, the pH‐responsive PQACs10‐co‐PEGMA10 micelles demonstrate a good ability to clear and prevent biofilms, holding promise for complete biofilm removal and a reduction in biofilm‐related infections.

Co-occurrence of adeno-associated virus 2 and human enteric adenovirus (group F) in wastewater after worldwide outbreaks of acute hepatitis of unknown etiology (AHUE)

In 2022, several cases of acute hepatitis of unknown etiology (AHUE) have been associated with Adeno-associated virus 2 (AAV-2) and the common childhood virus Adenovirus 41 (AdV-41). This outbreak has resulted in serious complications in patients which included 5 % of individuals requiring a liver transplant and 22 deaths. Before these AHUE cases, no previous information had been reported regarding the co-infections and co-occurrence of these two viruses in the human population. The present study utilized WBE tools to investigate the prevalence of AAV-2 and AdV-F (AdV-41 and AdV-40) in wastewater from two different waste-water treatment plants (WWTP) serving the city of Bloomington in Southern Indiana, USA. The concentrations of AAV-2 and AdV-F were quantified using digital PCR in weekly wastewater samples taken over the duration of 18 months. High levels of both viruses were observed in most of the samples where co-detection and correlation in the concentrations for AAV-2 and AdV-F were found to be significant (p < 0.01) throughout duration of the study. In addition, significant seasonal changes were observed in the viral concentrations of both viruses (P < 0.01), but these seasonal variations were different between WWTPs (p < 0.01). However, these seasonal variations in viral concentrations were similar for both viruses. The sequences of AdV-F and AAV were obtained from the wastewater samples and confirmed the detection of AAV-2, AdV-41, and AdV-40 in the samples analyzed. Even though our study was done after the 2022 outbreak of AHUE, our results demonstrated the persistence of infections with both viruses in the population. It also highlights the ongoing spread of both viruses in the population and the importance of WBE in surveillance of these viruses.

Cumulative influence of immunogenic factors, genetic variations, and protein modulations in subacute sclerosing panencephalitis (SSPE): A narrative review

AbstractSubacute sclerosing panencephalitis (SSPE) is a progressive and catastrophic neurodegenerative disorder due to persistent infection with the aberrant measles virus in the brain. The exact etiology of SSPE is still unknown, and early diagnosis remains a challenge, especially with the atypical presentations. The pathogenesis of SSPE involves a complex interplay between viral factors and immunological response of the host. The presenting review demonstrates an extensive glimpse of the immuno‐genetics of SSPE, exploring the single‐nucleotide polymorphisms (SNPs), genetic risk factors and immune responses that influence susceptibility and disease progression.

Hepatitis B virus: modes of transmission, immune pathogenesis, and research progress on therapeutic vaccines

Hepatitis B virus (HBV) infection affects 262 million people worldwide, leading to over 820,000 deaths annually. The reason HBV has been a persistent issue for decades is that it is a non-cytopathic, liver-specific virus with the ability for persistent infection, which cannot be completely eliminated by drugs, eventually progressing to cirrhosis and hepatocellular carcinoma (HCC). Although HBV seems to induce little innate immune activation, adaptive immune responses can mediate viral clearance and liver disease. Here, we review the epidemiology, natural history, lifecycle, and modes of transmission of HBV. We also pay particular attention to the adaptive and innate immune responses to HBV and the research progress on therapeutic vaccines, which may provide new insights for targeted HBV treatment.

Spatially controllable fluid hydrogel with in-situ electrospinning PCL/chitosan fiber for treating irregular wounds

Skin injuries sustained during exercise are often irregular in shape and frequently accompanied by infections. Bacteria residing in the crevices of these wounds can lead to persistent infections. Routine wound monitoring, which requires removing the wound dressing to assess recovery, is inconvenient and increases the risk of infection. To address this, we prepared a polyvinyl alcohol/polyhydroxylated fullerenes ((PVA/PHF) hydrogel with good fluidity and photothermal antibacterial properties, which can penetrate into the crevices of irregular wounds. After the hydrogel was applied to the wound, the hydrogel was locally defined by the polycaprolactone/Chitosan (PCL/CS) membrane of in-situ electrospinning, which effectively killed bacteria, and the healing efficiency was increased by 240 % in the wound healing experiment. The PVA/PHF hydrogel exhibits excellent electrical conductivity, making it suitable for real-time monitoring of human body motion as a strain sensor. This capability provides doctors with an accurate basis for wound assessment. At the same time, the hydrogel can achieve self-healing within 1.5 s and withstand up to 2200 % tensile strain, which can be used for large-scale motion monitoring of the human body. This flowable hydrogel, capable of penetrating wound crevices, offers a dual function of both treatment and monitoring.

Field-Applicable Loop-Mediated Isothermal Amplification for the Detection of Seven Common Human Papillomavirus Subtypes.

Persistent HPV infection is a major risk factor for the subsequent development of cervical cancer. LAMP is simple and suitable for field detection in the resource-limited settings. In this study, hydroxy naphthol blue (HNB)-based visual LAMP and evagreen-based fluorescent LAMP coupled with a microfluidic chip (LAMP-chip) were established for the field detection of seven subtypes of HPV. The analytical sensitivity was 19-233 copies/reaction. The overall clinical sensitivity was 97.35% for visual LAMP and 98.23% for LAMP-chip. Both LAMP assays exhibited 100% specificity and were completed in less than 50 min. Additionally, both assays did not require complicated nucleic acid extraction and purification steps. A complete quality control monitoring system (including internal control, positive quality control and negative control) in the LAMP assays further ensured the credibility of the results. Our findings demonstrated that the proposed LAMP assays have the potential to be applied in the testing of common HPV DNA in field investigations (visual LAMP) or within communities and primary health centers (LAMP-chip).

Inactivated vaccine dosage and serum IgG levels correlate with persistent COVID-19 infections in hematologic malignancy patients during the Omicron Surge in China

PurposeThe essence of this scholarly work was to carefully outline the key factors intensifying the virulence and protracted contagion of COVID-19, particularly among individuals afflicted with hematologic malignancies (HM), in an epoch predominantly governed by the Omicron variant.MethodsAdults with HM diagnosed with COVID-19 from November 2022 to February 2023 were monitored in this retrospective study. Patient blood samples yielded biochemical data, and COVID-19 was confirmed through RNA or antigen testing. The factors affecting severity and infection duration were examined using both univariate and multivariate logistic regression analyses. For calculating the overall survival probabilities, the Kaplan–Meier product limit approach was employed.ResultsIn the examined cohort, 133 individuals diagnosed with HM and concomitantly infected with COVID-19 were scrutinized. Of the participants, 29.3% (39 patients) were classified as Severe/Critical, while the other 70.7% (94 patients) were categorized as Non-severe. A significant difference was observed in vaccination status: 61.7% of patients in the Non-severe group had received at least a two-dose vaccine regimen, whereas 61.5% of the Severe/Critical group had either minimal or only one dose of vaccination. The data analysis revealed that elevated C-reactive protein levels (≥ 100 mg/L) significantly raised the risk of severe/critical conditions in HM patients with COVID-19, as determined by advanced multivariate logistic regression. The odds ratio was 3.415 with a 95% confidence interval of 1.294–9.012 (p = 0.013). Patients who continued to have positive nucleic acid tests and ongoing symptoms beyond 30 days were categorized as having a persistent infection, whereas those who achieved infection control within this timeframe were categorized as having infection recovery. Of the HM cohort, 11 did not survive beyond 30 days after diagnosis. The results from a competing risk model revealed that increased interleukin-6 levels (HR: 2.626, 95% CI: 1.361–5.075; p = 0.004) was significantly associated with persistent infection. Conversely, receiving more than two vaccine doses (HR: 0.366, 95% CI: 0.158–0.846; p = 0.019), and having high IgG levels (≥ 1000 mg/dl) (HR: 0.364, 95% CI: 0.167–0.791; p = 0.011), were associated with infection recovery. There was a notable disparity in survival rates between patients with persistent infections and infection recovery, with those in the non-persistent group demonstrating superior survival outcomes (P < 0.001).ConclusionsIn conclusion, the study determined that HM patients with COVID-19 and increased C-reactive protein levels had a higher likelihood of severe health outcomes. Persistent infection tended to be more prevalent in those with vaccine dosages (< 2 doses), lower IgG levels, and higher interleukin-6 levels.

Toll-like receptor 7 protects against intestinal inflammation and restricts the development of colonic tissue-resident memory CD8+ T cells.

The maintenance of intestinal homeostasis depends on a complex interaction between the immune system, intestinal epithelial barrier, and microbiota. Alteration in one of these components could lead to the development of inflammatory bowel diseases (IBD). Variants within the autophagy gene ATG16L1 have been implicated in susceptibility and severity of Crohn's disease (CD). Individuals carrying the risk ATG16L1 T300A variant have higher caspase 3-dependent degradation of ATG16L1 resulting in impaired autophagy and increased cellular stress. ATG16L1-deficiency induces enhanced IL-1β secretion in dendritic cells in response to bacterial infection. Infection of ATG16L1-deficient mice with a persistent strain of murine norovirus renders these mice highly susceptible to dextran sulfate sodium colitis. Moreover, persistent norovirus infection leads to intestinal virus specific CD8+ T cells responses. Both Toll-like receptor 7 (TLR7), which recognizes single-stranded RNA viruses, and ATG16L1, which facilitates the delivery of viral nucleic acids to the autolysosome endosome, are required for anti-viral immune responses. However, the role of the enteric virome in IBD is still poorly understood. Here, we investigate the role of TLR7 and ATG16L1 in intestinal homeostasis and inflammation. At steady state, Tlr7-/- mice have a significant increase in large intestinal lamina propria (LP) granzyme B+ tissue-resident memory CD8+ T (TRM) cells compared to WT mice, reminiscent of persistent norovirus infection. Deletion of Atg16l1 in myeloid (Atg16l1ΔLyz2 ) or dendritic cells (Atg16l1ΔCd11c ) leads to a similar increase of LP TRM. Furthermore, Tlr7-/- and Atg16l1ΔCd11c mice were more susceptible to dextran sulfate sodium colitis with an increase in disease activity index, histoscore, and increased secretion of IFN-γ and TNF-α. Treatment of Atg16l1ΔCd11c mice with the TLR7 agonist Imiquimod attenuated colonic inflammation in these mice. Our data demonstrate that ATG16L1-deficiency in myeloid and dendritic cells leads to an increase in LP TRM and consequently to increased susceptibility to colitis by impairing the recognition of enteric viruses by TLR7. In conclusion, the convergence of ATG16L1 and TLR7 signaling pathways plays an important role in the immune response to intestinal viruses. Our data suggest that activation of the TLR7 signaling pathway could be an attractive therapeutic target for CD patients with ATG16L1 risk variants.

Metabolomic Profiling Reveals Potential of Fatty Acids as Regulators of Stem-like Exhausted CD8 T Cells During Chronic Viral Infection.

This study examines systemic metabolite changes during acute and chronic viral infections. Notably, we identified an early, transient nutrient shift in chronic infection, marked by an increase in medium- and long-chain fatty acid related species. Concomitantly, a virus-specific stem-like T cell population, essential for maintaining other T cells, displayed high lipid avidity and was capable of metabolizing exogenous fatty acids. Administering fatty acids late in chronic infection, when endogenous lipid levels had normalized, expanded this stem-like T cell population and enhanced their mitochondrial fitness. These findings highlight the potential role of fatty acids in regulating stem-like T cells in chronic settings and offer a valuable resource for studying other metabolic signatures in both acute and persistent infections.

Bilateral chronic cavitary pulmonary aspergillomas in an adult patient with recurrent tuberculosis: a case report and literature review

BackgroundAspergillomas are globular growths of Aspergillus fumigatus, a benign aspergillosis of the lungs. It usually affects patients who are immunocompromised and have anatomically defective lung structures. The majority of aspergilloma cases are asymptomatic, despite the fact that 10% of cases spontaneously resolve. Most patients do not have any symptoms from their lesions. Direct serological or microbiological evidence of an Aspergillus species along with radiologic evidence is required for the diagnosis of an aspergilloma.CaseWe describe a 35-year-old adult Oromo male patient who had been experiencing night sweats, an intermittent productive cough with sparse whitish sputum, loss of appetite, and easy fatigability for 3 months. At 5 years prior, he received treatment for pulmonary tuberculosis that was smear-positive and was subsequently certified healed. Objectively, he was tachypneic and had intercostal, subcostal, and supraclavicular retractions with symmetric chest movement. A high-resolution computed tomography scan revealed bilateral apical cavitary lesions with core soft tissue attenuating spherical masses and an air crescentic sign suggestive of aspergillomas, which were confirmed by sputum light microscopic examination. The patient was managed with antibiotics and antifungals.ConclusionAspergilloma is a symptom of chronic pulmonary aspergillosis, a category of lung disorders caused by a persistent Aspergillus infection. Primary aspergillomas are uncommon and frequently occur in people with compromised immune systems. A prolonged cough, fever, chest pain, and hemoptysis are all symptoms of pulmonary aspergillomas. The majority of the time, pulmonary aspergillosis is difficult to identify. Despite high mortality and morbidity rates, surgery is still the most effective treatment for pulmonary aspergilloma.

Role of DNA Double-Strand Break Formation in Gyrase Inhibitor-Mediated Killing of Nonreplicating Persistent Mycobacterium tuberculosis in Caseum.

Tuberculosis is the leading cause of mortality by infectious agents worldwide. The necrotic debris, known as caseum, which accumulates in the center of pulmonary lesions and cavities is home to nonreplicating drug-tolerant Mycobacterium tuberculosis that presents a significant hurdle to achieving a fast and durable cure. Fluoroquinolones such as moxifloxacin are highly effective at killing this nonreplicating persistent bacterial population and boosting TB lesion sterilization. Fluoroquinolones target bacterial DNA gyrase, which catalyzes the negative supercoiling of DNA and relaxes supercoils ahead of replication forks. In this study, we investigated the potency of several other classes of gyrase inhibitors against M. tuberculosis in different states of replication. In contrast to fluoroquinolones, many other gyrase inhibitors kill only replicating bacterial cultures but produce negligible cidal activity against M. tuberculosis in ex vivo rabbit caseum. We demonstrate that while these inhibitors are capable of inhibiting M. tuberculosis gyrase DNA supercoiling activity, fluoroquinolones are unique in their ability to cleave double-stranded DNA at low micromolar concentrations. We hypothesize that double-strand break formation is an important driver of gyrase inhibitor-mediated bactericidal potency against nonreplicating persistent M. tuberculosis populations in the host. This study provides general insight into the lesion sterilization potential of different gyrase inhibitor classes and informs the development of more effective chemotherapeutic options against persistent mycobacterial infections.

Antibacterial Therapeutic Ions Incorporation into Bioactive Glasses as a Winning Strategy against Antibiotic Resistance

AbstractThis work focuses on combating bacterial infections in bone tissue using metal elements embedded in bioactive glass. While there is an urgent need for alternative methods with a shrinking number of effective treatment options untouched by antimicrobial resistance, it is crucial to first understand the mechanisms of pathogenesis, persistence, and bacterial resistance in skeletal infection, and then develop effective counterstrategies and innovative alternatives. This review considers the role of antimicrobial metal ions, their mechanism of action, and their incorporation into bioactive glass formulations as these materials can serve as delivery platforms with the least possible complexities. Furthermore, the bacterial infection risk in bone is also examined with specific attention to antibiotic resistance and biofilm formation. This review sheds light on the most promising materials as novel antibacterial agents by presenting a wide range of possible bioactive glass formulations equipped with potential antibacterial ions and in vitro/ in vivo insights, and it also reinforces the importance of continuing studies to develop multi‐faceted antibacterial bioactive glasses.

HPV16 E6-induced M2 macrophage polarization in the cervical microenvironment via exosomal miR-204-5p

The persistent infection of high-risk human papillomavirus (HPV) and the progression of cervical cancer necessitate the involvement of microenvironmental immunity. As cervical lesions advance, there is an observed increase in the infiltration of type 2 (M2) macrophages. However, the precise mechanism driving this increased infiltration of M2 macrophages remains unclear. In this study, we investigated the role of exosomes in polarising M2 macrophages in cervical lesions associated with HPV E6. Through the analysis of bioinformatics data and clinical specimens, we discovered a positive correlation between HPV E6/E7 mRNA copy number and the level of M2 macrophage infiltration. Exosomes derived from HPV E6 overexpressed (HPV E6+) cervical squamous cell carcinoma (CESC) cells were found to induce the polarisation of macrophages towards M2 type. Specifically, miR-204-5p, enriched in HPV E6 + CESC exosomes, was transported into macrophages and triggered M2 macrophage polarisation by inhibiting JAK2. The clinical relevance of exosomal miR-204-5p in the progression of cervical lesions was validated through serum samples from 35 cases. Exosomal miR-204-5p emerges as a critical factor influencing M2 macrophage polarisation and is correlated with the severity of cervical lesions. Consequently, miR-204-5p could be used as a potential treatment and a candidate biomarker for cervical lesions.